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Risk of cardiovascular diseases after Hodgkin lymphoma treatment van Nimwegen, F.A.

2016

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van Nimwegen, F. A. (2016). Risk of cardiovascular diseases after Hodgkin lymphoma treatment.

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Chapter 4

ƌĂĚŝĂƟŽŶĚŽƐĞͲƌĞƐƉŽŶƐĞƌĞůĂƟŽŶƐŚŝƉĨŽƌƌŝƐŬŽĨ

ĐŽƌŽŶĂƌǇŚĞĂƌƚĚŝƐĞĂƐĞŝŶƐƵƌǀŝǀŽƌƐŽĨ,ŽĚŐŬŝŶůǇŵƉŚŽŵĂ

:ŽƵƌŶĂůŽĨůŝŶŝĐĂůKŶĐŽůŽŐǇϮϬϭϱ͖ϯϰ;ϯͿ͗ϮϯϱͲϮϰϯ

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4 /ŶƚƌŽĚƵĐƟŽŶ

,ŽĚŐŬŝŶ ůǇŵƉŚŽŵĂ ;,>Ϳ ƚƌĞĂƚŵĞŶƚ ŚĂƐ ŝŵƉƌŽǀĞĚ ŽǀĞƌ ƌĞĐĞŶƚ ĚĞĐĂĚĞƐ͕ ůĞĂĚŝŶŐ ƚŽ Ă ϭϬͲ ǇĞĂƌ ƐƵƌǀŝǀĂů ƌĂƚĞ ŽĨ ŽǀĞƌ ϴϬй1_{͘ ,ŽǁĞǀĞƌ͕ ƌĂĚŝŽƚŚĞƌĂƉǇ ĂŶĚ ĐŚĞŵŽƚŚĞƌĂƉǇ ĂƌĞ ĂƐƐŽĐŝĂƚĞĚ} ǁŝƚŚ ŝŶĐƌĞĂƐĞĚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ŵŽƌďŝĚŝƚǇ ĂŶĚ ŵŽƌƚĂůŝƚǇ ŝŶ ůŽŶŐͲƚĞƌŵ ƐƵƌǀŝǀŽƌƐ2-7_{͘ ůƚŚŽƵŐŚ} ƌĂĚŝĂƟŽŶĚŽƐĞƐĂŶĚƚĂƌŐĞƚǀŽůƵŵĞƐŚĂǀĞďĞĞŶƌĞĚƵĐĞĚŽǀĞƌƚŚĞƉĂƐƚĚĞĐĂĚĞƐ͕ŵĞĚŝĂƐƟŶĂů ƌĂĚŝŽƚŚĞƌĂƉǇŝƐƐƟůůŝŶĚŝĐĂƚĞĚĨŽƌĂƐƵďƐƚĂŶƟĂůƉƌŽƉŽƌƟŽŶŽĨƉĂƟĞŶƚƐ8,9_{͕ǁŚŝĐŚŵĂǇƌĞƐƵůƚŝŶ} ĐŽŶƐŝĚĞƌĂďůĞƌĂĚŝĂƟŽŶĞǆƉŽƐƵƌĞƚŽƚŚĞŚĞĂƌƚ͘ sĞƌǇ ĨĞǁ ƐƚƵĚŝĞƐ ŚĂǀĞ ĞǆĂŵŝŶĞĚ ƚŚĞ ĚŽƐĞͲƌĞƐƉŽŶƐĞ ƌĞůĂƟŽŶƐŚŝƉ ĨŽƌ ĐĂƌĚŝĂĐ ƌĂĚŝĂƟŽŶ ĂŶĚƌŝƐŬŽĨĐŽƌŽŶĂƌǇŚĞĂƌƚĚŝƐĞĂƐĞ;,ͿĂŌĞƌƌĂĚŝŽƚŚĞƌĂƉǇ͘ƌĞĐĞŶƚƐƚƵĚǇŽĨĂƌďǇĞƚĂů10 ƐŚŽǁĞĚĂůŝŶĞĂƌĚŽƐĞͲƌĞƐƉŽŶƐĞƌĞůĂƟŽŶƐŚŝƉďĞƚǁĞĞŶƌĂĚŝĂƟŽŶĚŽƐĞƚŽƚŚĞŚĞĂƌƚĂŶĚ, ƌŝƐŬŝŶďƌĞĂƐƚĐĂŶĐĞƌƐƵƌǀŝǀŽƌƐĨŽƌĂƌĞůĂƟǀĞůǇůŽǁƌĂŶŐĞŽĨŵĞĂŶŚĞĂƌƚĚŽƐĞ;D,Ϳ;ƌĂŶŐĞ͗ Ϭ͘ϬϯͲϮϳ͘ϳ'Ǉ͕ĂǀĞƌĂŐĞ͗ϱ'ǇͿ͘/Ŷ,>ƉĂƟĞŶƚƐ͕ǁŚŽŐĞŶĞƌĂůůǇƌĞĐĞŝǀĞŵƵĐŚŚŝŐŚĞƌD,ƐĂŶĚ ĂƌĞƵƐƵĂůůǇǇŽƵŶŐĞƌĂƚĚŝĂŐŶŽƐŝƐƚŚĂŶďƌĞĂƐƚĐĂŶĐĞƌƉĂƟĞŶƚƐ͕ƚŚĞƐŚĂƉĞŽĨƚŚĞĚŽƐĞͲƌĞƐƉŽŶƐĞ ƌĞůĂƟŽŶƐŚŝƉŚĂƐŶŽƚďĞĞŶƐƚƵĚŝĞĚ͘ ^ĐŚĞůůŽŶŐĞƚĂů11_{ĂŶĚDƵůƌŽŽŶĞǇĞƚĂů}12_{ŽďƐĞƌǀĞĚĂŶĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶĐĂƌĚŝŽǀĂƐĐƵůĂƌ} ĚŝƐĞĂƐĞƐ ĂŶĚ ƉƌĞƐĐƌŝďĞĚ ŵĞĚŝĂƐƟŶĂů ƌĂĚŝĂƟŽŶ ĚŽƐĞ ĂŶĚ D,͕ ĂŵŽŶŐ ĐŚŝůĚŚŽŽĚ ,> ;ĂŶĚ ŽƚŚĞƌĐĂŶĐĞƌͿƐƵƌǀŝǀŽƌƐ͖ŚŽǁĞǀĞƌ͕ƚŚĞƐŚĂƉĞŽĨƚŚĞƌĂĚŝĂƟŽŶĚŽƐĞͲƌĞƐƉŽŶƐĞƌĞůĂƟŽŶƐŚŝƉĂŶĚ ĞǆĐĞƐƐƌĞůĂƟǀĞƌŝƐŬƐ;ZZƐͿǁĞƌĞŶŽƚĚĞƐĐƌŝďĞĚ͘ /Ŷ ĂĚĚŝƟŽŶ ƚŽ ƚŚĞ ƐŚĂƉĞ ŽĨ ƚŚĞ ĚŽƐĞͲƌĞƐƉŽŶƐĞ ƌĞůĂƟŽŶƐŚŝƉ͕ ƚŚĞ ƌŽůĞƐ ŽĨ ĞƐƚĂďůŝƐŚĞĚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƌŝƐŬĨĂĐƚŽƌƐĂŶĚůŝĨĞƐƚǇůĞŽŶ,ƌŝƐŬŚĂǀĞŚĂƌĚůǇďĞĞŶƐƚƵĚŝĞĚĂŵŽŶŐ ,>ƐƵƌǀŝǀŽƌƐ4,5,13_{͘dŚĞƌĞĨŽƌĞ͕ƚŚĞĂŝŵŽĨƚŚŝƐƐƚƵĚǇǁĂƐƚŽĂƐƐĞƐƐƚŚĞƐŚĂƉĞŽĨƚŚĞĚŽƐĞͲƌĞƐƉŽŶƐĞ} ĐƵƌǀĞ ĨŽƌ ĐĂƌĚŝĂĐ ƌĂĚŝĂƟŽŶ ĚŽƐĞ ĂŶĚ ƚŚĞ ƌŝƐŬ ŽĨ , ŝŶ ĂĚŽůĞƐĐĞŶƚ ĂŶĚ ĂĚƵůƚ ,> ƐƵƌǀŝǀŽƌƐ ĂŶĚƚŽŝŶǀĞƐƟŐĂƚĞƚŚĞƌŽůĞŽĨĐŚĞŵŽƚŚĞƌĂƉǇ͕ůŝĨĞƐƚǇůĞĂŶĚŽƚŚĞƌĞƐƚĂďůŝƐŚĞĚĐĂƌĚŝŽǀĂƐĐƵůĂƌ disease (CVD) risk factors.

WĂƟĞŶƚƐĂŶĚŵĞƚŚŽĚƐ

^ƚƵĚǇƉŽƉƵůĂƟŽŶ

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ǁĂƐĚĞĮŶĞĚĂƐƚŚĞĚĂƚĞŽĨ,ĨŽƌƚŚĞĐĂƐĞƐ͕ŽƌƚŚĞĚĂƚĞŽĨ,>ĚŝĂŐŶŽƐŝƐƉůƵƐĂƟŵĞŝŶƚĞƌǀĂů ĞƋƵĂů ƚŽ ƚŚĞ ŝŶƚĞƌǀĂů ĨƌŽŵ ƚŚĞ ĚĂƚĞ ŽĨ ,> ĚŝĂŐŶŽƐŝƐ ƚŽ ƚŚĞ ĚĂƚĞ ŽĨ , ĚŝĂŐŶŽƐŝƐ ŽĨ ƚŚĞ ĐŽƌƌĞƐƉŽŶĚŝŶŐĐĂƐĞĨŽƌŵĂƚĐŚĞĚĐŽŶƚƌŽůƐ.

Cases and controls

ĂƐĞƐ ;ŶсϯϮϱͿ ǁĞƌĞ ƉĂƟĞŶƚƐ ǁŚŽ ĚĞǀĞůŽƉĞĚ , ŝŶ ƚŚĞ ĨŽƌŵ ŽĨ ĞŝƚŚĞƌ ƐǇŵƉƚŽŵĂƟĐ ŵǇŽĐĂƌĚŝĂůŝŶĨĂƌĐƟŽŶŽƌĂŶŐŝŶĂƉĞĐƚŽƌŝƐƌĞƋƵŝƌŝŶŐŝŶƚĞƌǀĞŶƟŽŶ;ŽŵŵŽŶdĞƌŵŝŶŽůŽŐǇƌŝƚĞƌŝĂ ĨŽƌĚǀĞƌƐĞǀĞŶƚƐǀĞƌƐŝŽŶϰ͘Ϭ͗ŐƌĂĚĞшϮ͕ƐĞĞƐƵƉƉůĞŵĞŶƚĂůƚĞǆƚϭͿ18_{ĂƐƚŚĞŝƌĮƌƐƚĐůŝŶŝĐĂůůǇ} ƐŝŐŶŝĮĐĂŶƚŚĞĂƌƚĚŝƐĞĂƐĞ͘ĂƐĞƐǁĞƌĞŝĚĞŶƟĮĞĚĨƌŽŵŵĞĚŝĐĂůƌĞĐŽƌĚƐŽƌƉŽƐƚĂůƋƵĞƐƟŽŶŶĂŝƌĞƐ ĐŽŵƉůĞƚĞĚďǇƚŚĞŝƌŐĞŶĞƌĂůƉƌĂĐƟƟŽŶĞƌƐ͘&ŽůůŽǁͲƵƉǁĂƐĐŽŵƉůĞƚĞƵƉƚŽKĐƚŽďĞƌϮϬϭϯ͘For ĞĂĐŚĐĂƐĞǁŝƚŚ,͕ǁĞĂƩĞŵƉƚĞĚƚŽƐĞůĞĐƚϰĐŽŶƚƌŽůƐĨƌŽŵƚŚĞĐŽŚŽƌƚ͕ŝŶĚŝǀŝĚƵĂůůǇŵĂƚĐŚĞĚ ŽŶƐĞǆ͕ĂŐĞĂƚ,>ĚŝĂŐŶŽƐŝƐ;чϭǇĞĂƌͿĂŶĚĚĂƚĞŽĨ,>ĚŝĂŐŶŽƐŝƐ;чϯǇĞĂƌƐͿ͘ŽŶƚƌŽůƐŚĂĚƚŽďĞ ĨƌĞĞŽĨĂŶǇĐĂƌĚŝĂĐĚŝƐĞĂƐĞŐƌĂĚĞшϮĂƚƚŚĞĐƵƚͲŽīĚĂƚĞ͘/ŶƚŽƚĂů͕ϭ͕ϮϬϰĐŽŶƚƌŽůƐǁĞƌĞŵĂƚĐŚĞĚ to the cases. ĂƚĂĐŽůůĞĐƟŽŶ ĞƚĂŝůĞĚŝŶĨŽƌŵĂƟŽŶŽŶƚƌĞĂƚŵĞŶƚ;ŝŶĐůƵĚŝŶŐƌĂĚŝĂƟŽŶĚŽƐĞƐĂŶĚĮĞůĚƐĂŶĚĐƵŵƵůĂƟǀĞĚŽƐĞƐ ŽĨĐǇƚŽƚŽǆŝĐĚƌƵŐƐͿ͕ŵĞĚŝĐĂůŚŝƐƚŽƌǇ͕ŵĞĚŝĐĂƟŽŶƵƐĞ͕ƐŵŽŬŝŶŐĂŶĚĞƐƚĂďůŝƐŚĞĚĐĂƌĚŝŽǀĂƐĐƵůĂƌ ƌŝƐŬ ĨĂĐƚŽƌƐ ďŽƚŚ Ăƚ ĚŝĂŐŶŽƐŝƐ ŽĨ ,> ĂŶĚ ĚƵƌŝŶŐ ĨŽůůŽǁͲƵƉ ǁĂƐ ĐŽůůĞĐƚĞĚ ĨƌŽŵ ŵĞĚŝĐĂů ƌĞĐŽƌĚƐĂŶĚƌĂĚŝĂƟŽŶĐŚĂƌƚƐ͘/ŶĂĚĚŝƟŽŶ͕ĂƋƵĞƐƟŽŶŶĂŝƌĞŽŶĞƐƚĂďůŝƐŚĞĚĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬ ĨĂĐƚŽƌƐĂŶĚůŝĨĞƐƚǇůĞǁĂƐŵĂŝůĞĚƚŽĂůůƉĂƟĞŶƚƐƐƟůůĂůŝǀĞŝŶϮϬϭϯ;ŶсϰϳϱͿŝŶƚŚƌĞĞŽĨƚŚĞĮǀĞ ĐĞŶƚĞƌƐ ;ƌĞƐƉŽŶƐĞ ƌĂƚĞ͗ ϳϬйͿ͘ WĂƟĞŶƚƐ ǁĞƌĞ ĚĞĮŶĞĚ ĂƐ ŚĂǀŝŶŐ Ă ƌŝƐŬ ĨĂĐƚŽƌ ǁŚĞŶ ƚŚĞ ƌŝƐŬ ĨĂĐƚŽƌĐŽŶĐĞƌŶĞĚǁĂƐĚŝĂŐŶŽƐĞĚƉƌŝŽƌƚŽ,ͬĐƵƚͲŽīĚĂƚĞ͘dŚĞĞƚŚŝĐƐƌĞǀŝĞǁďŽĂƌĚŽĨdŚĞ EĞƚŚĞƌůĂŶĚƐĂŶĐĞƌ/ŶƐƟƚƵƚĞĂƉƉƌŽǀĞĚƚŚŝƐƐƚƵĚǇ͘

Mean heart dose

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4

^ƚĂƟƐƟĐĂůĂŶĂůǇƐŝƐ KĚĚƐƌĂƟŽƐĨŽƌ,ĨŽƌĚŝīĞƌĞŶƚůĞǀĞůƐŽĨĞĂĐŚĨĂĐƚŽƌǁĞƌĞĐĂůĐƵůĂƚĞĚƵƐŝŶŐĐŽŶĚŝƟŽŶĂůůŽŐŝƐƟĐ ƌĞŐƌĞƐƐŝŽŶŽŶƐĞƚƐŽĨŝŶĚŝǀŝĚƵĂůĐĂƐĞƐĂŶĚƚŚĞŝƌŵĂƚĐŚĞĚĐŽŶƚƌŽůƐ͕ĂŶĚǁĞƌĞŝŶƚĞƌƉƌĞƚĞĚĂƐƌĂƚĞ ƌĂƟŽ͛Ɛ;ZZƐͿ͘ϵϱйĐŽŶĮĚĞŶĐĞŝŶƚĞƌǀĂůƐ;/ͿĨŽƌĨĂĐƚŽƌƐǁŝƚŚƚǁŽůĞǀĞůƐƵƐĞĚƚŚĞtĂůĚŵĞƚŚŽĚ͘ ϵϱй/ƐĨŽƌĨĂĐƚŽƌƐǁŝƚŚхϮůĞǀĞůƐƵƐĞĚƚŚĞĂŵŽƵŶƚŽĨŝŶĨŽƌŵĂƟŽŶŝŶĞĂĐŚĐĂƚĞŐŽƌǇ͕ŝŶĐůƵĚŝŶŐ ƚŚĞƌĞĨĞƌĞŶĐĞĐĂƚĞŐŽƌǇ;ƐŽĐĂůůĞĚŇŽĂƟŶŐĂďƐŽůƵƚĞƌŝƐŬƐͿ21_{. DƵůƟǀĂƌŝĂďůĞƌĞŐƌĞƐƐŝŽŶǁĂƐƵƐĞĚ} ƚŽĂƐƐĞƐƐĂŶĚĐŽŶƚƌŽůĨŽƌĐŽŶĨŽƵŶĚŝŶŐĂŶĚƚŽĞǀĂůƵĂƚĞŝŶƚĞƌĂĐƟŽŶƐďĞƚǁĞĞŶƌĂĚŝĂƟŽŶĚŽƐĞ and other factors.

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Table 1:WĂƟĞŶƚĐŚĂƌĂĐƚĞƌŝƐƟĐƐ ĂƐĞƐΎ ŽŶƚƌŽůƐΎ N % N % Total 325 100 1208 100 ^Ğǆ DĂůĞƐ 236 72.6 889 73.9 &ĞŵĂůĞƐ 89 27.4 319 26.4 Age at diagnosis (median, IQR) 32.3 24.5-39.4 32.2 24.4-39.6

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4

Mean heart dose (median, IQR) 21.7 18.4-25.7 20.2 17.5-24.8

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(10)

(11)

Table 2: ZŝƐŬŽĨĐ Ž ƌŽ ŶĂƌǇŚĞĂƌƚĚŝƐĞĂƐĞĂĐĐ Žƌ ĚŝŶŐƚ Ž,ŽĚŐŬŝŶůǇŵƉŚŽŵĂƚ ƌĞ Ăƚ ŵĞŶ ƚ ŶĂƐĞƐ ŶŽŶ ƚƌ ŽůƐ Crude ĚũƵƐ ƚĞĚ ¥ dƌ ĞĂ ƚŵĞŶ ƚĨ ĂĐƚ Žƌ ;ƚ Ž ƚĂů͗ϯϮϱͿ ;ƚ Ž ƚĂů͗ϭϮϬϰͿ RR ϵϱй/ pR R ϵϱй/ p ZĂĚŝŽƚŚĞƌ ĂƉ Ǉ No 10 111 1 re f 1 re f Ye s 315 1093 3.16 1.63-6.14 0.001 2.99 1.52-5.85 0.001 DĞĚŝĂƐ ƟŶĂůƌ ĂĚŝŽƚŚĞƌ ĂƉ Ǉ No 29 251 1 re f 1 re f Ye s 296 953 2.71 1.79-4.08 фϬ͘ϬϬϭ 2.63 1.74-3.99 фϬ͘ϬϬϭ WĂ ƌĂ ͲĂŽƌƟĐƌ ĂĚŝŽƚŚĞƌ ĂƉ Ǉ No 168 633 1 re f 1 re f Ye s 157 571 1.05 0.81-1.35 0.712 0.99 0.76-1.28 0.927 ^ƉůĞŶŝĐƌ ĂĚŝŽƚŚĞƌ ĂƉ Ǉ No 229 878 1 re f 1 re f Ye s 96 326 1.13 0.86-1.50 0.372 1.07 0.80-1.42 0.656 Wƌ ĞƐĐƌŝďĞĚŵĞĚŝĂƐ ƟŶĂůĚŽƐĞ Ϭ' Ǉ;ŶŽŵĞĚŝĂƐ ƟŶĂůZ dͿ 29 251 1.00 0.68-1.48 1.00 0.67-1.48 ϭϱͲϮϰ' Ǉ 5 28 1.49 0.57-3.89 1.51 0.58-3.96 ϮϱͲϯϰ' Ǉ 26 97 2.31 1.50-3.57 2.30 1.49-3.56 ϯϱͲϯϵ' Ǉ 156 535 2.56 2.12-3.08 2.52 2.10-3.03 ϰϬͲϰϱ' Ǉ 109 293 3.12 2.50-3.90 фϬ͘ϬϬϭ Τ 3.03 2.41-3.82 фϬ͘ϬϬϭ Τ

Mean heart dose

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)